Antigen-presenting cells (APCs) process foreign antigens into peptides that are bound by class II molecules of the Major Histocompatibility Complex and expressed on the plasma membrane as the ligand for clonal activation of CD4+ T lymphocytes. The function of APCs is critical in the initiation and regulation of immune responses. The long range goal of this research is to identify the class II+ cell types which perform this function in vivo. This will be accomplished using well- characterized class II transgenic mice and allogeneic bone marrow- reconstituted SCID mice that express a particular class II molecule or haplotype on different cell types. These animals will be immunized with soluble protein antigens that can be internalized via either non-specific mechanisms or receptor-mediated endocytosis, with particulate proteins requiring phagocytosis and with intracellular parasites. The working hypothesis is that foreign antigens must compete with self proteins for the peptide binding site on a class II molecule; and, therefore, a class II+ cell can be an effective APC only for those antigens that it can concentrate by receptor-mediated endocytosis or that reach high concentrations as a result of intracellular growth. Operationally this would mean that antigen-specific B cells are the requisite APCs for soluble protein antigens in vivo, while macrophages may be the principle APCs for particulate antigens and obligate intracellular parasites. A knowledge of which class II+ cell types function as APCs in vivo for the activation CD4+ T cells to different forms of antigen will aid in the design and delivery of new synthetic vaccines.